AO-176 in Multiple Solid Tumor Malignancies

• ClinicalTrials.gov Identifier: NCT03834948
• Recruitment Status: Active, not recruiting
• First Posted: February 8, 2019
• Last Update Posted: August 5, 2022
• Sponsor: Arch Oncology
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Arch Oncology

Tracking Information

• First Submitted Date: February 4, 2019
• First Posted Date: February 8, 2019
• Last Update Posted Date: August 5, 2022
• Actual Study Start Date: February 4, 2019
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 3, 2021)

• Safety of AO-176 assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
  Evaluate the safety of AO-176 measured by the number adverse events, serious adverse events and lab abnormalities.
• Safety of AO-176 and paclitaxel assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
  Evaluate the safety of AO-176 in combination with paclitaxel measured by the number adverse events, serious adverse events and lab abnormalities.
• Safety of AO-176 and pembrolizumab assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
  Evaluate the safety of AO-176 in combination with pembrolizumab measured by the number adverse events, serious adverse events and lab abnormalities.

Original Primary Outcome Measures (submitted: February 6, 2019)

Safety Of AO-176 assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]

Evaluate the safety of AO-176 measured by the number adverse events, serious adverse events and lab abnormalities.

Current Secondary Outcome Measures (submitted: July 3, 2021)

• AO-176 anti-tumor activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]
  Evaluate objective response rate of AO-176 using RECIST v1.1 and iRECIST.
• AO-176 + paclitaxel anti-tumor activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]
  Evaluate objective response rate of AO-176 in combination with paclitaxel using RECIST v1.1 and iRECIST.
• AO-176 + pembrolizumab anti-tumor activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]
  Evaluate objective response rate of AO-176 in combination with pembrolizumab using RECIST v1.1 and iRECIST.

Original Secondary Outcome Measures (submitted: February 6, 2019)

AO-176 Anti-Tumor Activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]

Evaluate Objective response rate of AO-176 using RECIST and iRECIST.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: AO-176 in Multiple Solid Tumor Malignancies
• Official Title: A Phase 1/2 Multicenter, Open-Label, Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of AO-176
• Brief Summary: This is a first-in-human, Phase 1/2 multi-center, open-label, dose escalation and expansion study of AO-176 which will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and clinical effects of AO-176 in patients with advanced solid tumors.

Detailed Description

This is a first-in-human, Phase 1/2 multicenter, open-label, dose escalation and expansion study of AO-176 in patients with solid tumors. Part A of this study will examine escalating repeat doses of AO-176 monotherapy in patients with select advanced solid tumors, including epithelial ovarian carcinoma (EOC), which will include primary peritoneal and fallopian tube carcinoma; squamous cell carcinoma of the head and neck; endometrial carcinoma; castration resistant prostate cancer; non-small cell lung adenocarcinoma; papillary thyroid carcinoma; pleural or peritoneal malignant mesothelioma; and gastroesophageal adenocarcinoma, for which standard therapy proven to provide clinical benefit does not exist or is no longer effective.

Part B and Part C of this study will examine escalating repeat doses of AO-176 in combination with paclitaxel (Part B) or pembrolizumab (Part C) in platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma; endometrial carcinoma; and gastric adenocarcinoma/gastroesophageal adenocarcinoma.

The monotherapy and combination dose escalation portions of the study utilize a classic 3+3 design, with enrollment of 3 patients per cohort and expansion of the cohort in the event of a dose-limiting toxicity (DLT).

Once the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) has been established in dose escalation, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176 as monotherapy, in combination with paclitaxel, and in combination with pembrolizumab.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Each dose escalation cohort will initially recruit 3 patients to receive AO-176 or AO-176 + paclitaxel or AO-176 + pembrolizumab in a standard 3+3 design; the cohort will be expanded in the event of a DLT.

Once the MTD/RP2D has been established for monotherapy, AO-176 + paclitaxel or AO-176 + pembrolizumab, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Solid Tumor

Intervention

• Drug: AO-176
  Humanized monoclonal antibody (mAb) targeting CD47
• Drug: AO-176 + Paclitaxel
  Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel
• Drug: AO-176 + Pembrolizumab
  Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab

Study Arms

• Experimental: AO-176 Dose Escalation
  Each dose escalation cohort will initially recruit 3 patients to receive AO-176 in a standard 3+3 design; cohorts will be expanded in the event of a DLT.
  Intervention: Drug: AO-176
• Experimental: AO-176 Dose Expansion
  Once the MTD/RP2D has been established, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176.
  Intervention: Drug: AO-176
• Experimental: AO-176 + Paclitaxel Dose Escalation
  Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and paclitaxel in a standard 3+3 design; cohorts will be expanded in the event of a DLT.
  Intervention: Drug: AO-176 + Paclitaxel
• Experimental: AO-176 + Paclitaxel Dose Expansion
  Once the MTD/RP2D has been established, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176 + paclitaxel.
  Intervention: Drug: AO-176 + Paclitaxel
• Experimental: AO-176 + Pembrolizumab Dose Escalation
  Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and pembrolizumab in a standard 3+3 design; cohorts will be expanded in the event of a DLT.
  Intervention: Drug: AO-176 + Pembrolizumab
• Experimental: AO-176 + Pembrolizumab Dose Expansion
  Once the MTD/RP2D has been established, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176 + pembrolizumab.
  Intervention: Drug: AO-176 + Pembrolizumab

• Publications *: Andrejeva G, Capoccia BJ, Hiebsch RR, Donio MJ, Darwech IM, Puro RJ, Pereira DS. Novel SIRPalpha Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells. J Immunol. 2021 Feb 15;206(4):712-721. doi: 10.4049/jimmunol.2001019. Epub 2021 Jan 11.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 3, 2021): 183
• Original Estimated Enrollment (submitted: February 6, 2019): 90
• Estimated Study Completion Date: March 2023
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria

1. Select advanced solid tumor for which standard therapy proven to provide clinical benefit does not exist, or is no longer effective

   Part A:

   • Epithelial ovarian carcinoma (EOC)
   • Endometrial carcinoma
   • Castration resistant prostate cancer
   • Non-small cell lung adenocarcinoma
   • Papillary thyroid carcinoma
   • Malignant mesothelioma (pleural or peritoneal)
   • Gastroesophageal adenocarcinoma
   • Squamous cell carcinoma of the head and neck

   Part B and Part C:

   • Platinum-resistant EOC (including fallopian tube or primary peritoneal cancer)
   • Endometrial carcinoma
   • Gastric adenocarcinoma/gastroesophageal adenocarcinoma
2. Measurable disease
3. ECOG status 0-1
4. Resolution of prior-therapy-related adverse effects
5. Minimum of 4 weeks or 5 half-lives since last dose of cancer therapy

Key Exclusion Criteria:

1. Previous hypersensitivity reaction to treatment with another monoclonal antibody
2. Unresolved hypersensitivity to paclitaxel or any of its excipients (Part B only). Patients who have been desensitized may participate.

3. Part C Only

   1. History of interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
   2. History of immune mediated colitis, hepatitis, endocrinopathies, nephritis or significant immune mediated skin reactions such as toxic epidermal necrolitis or Stevens -Johnson Syndrome
   3. History of any autoimmune disease which required systemic therapy* in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) including but not limited to: i. Inflammatory bowel disease (including ulcerative colitis and Crohn's Disease) ii. Rheumatoid arthritis iii. Systemic progressive sclerosis (scleroderma) iv. Systemic lupus erythematosus v. Autoimmune vasculitis (e.g. Wegener's granulomatosis) *Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed)
4. Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4 etc.) within 4 weeks prior to the start of study drug
5. Prior treatment with a CD47-targeted therapy
6. Prior organ or stem cell transplant

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03834948
• Other Study ID Numbers: AO-176-101; KEYNOTE-C49 ( Other Identifier: Merck Sharp & Dohme Corp. )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Arch Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Arch Oncology
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Study Director: Benajmin Oshrine, MD; Arch Oncology

• PRS Account: Arch Oncology
• Verification Date: August 2022